**4. Histopathology of atherosclerotic disease**

It has been well established that carotid stenosis tends to occur at the bifurcation, which corresponds to vascular shear stresses as determined by *in vivo* measurements and *in vitro* flow models. The healthy artery is composed of three distinct layers, the tunica intima, tunica media and tunica adventitia, as seen from the lumen to the outer vessel wall. The tunica intima is composed of a luminal endothelial layer consisting of an internal elastic lamina and a fibro‐ collagenous tissue layer, the latter two of which are thrombogenic. This tissue layer is covered externally by the tunica media consisting of smooth muscle cells followed by a fibrocollage‐ nous layer composed of the external elastic lamina and an external fibrous serosa layer, which composes the tunica adventitia layer. Carotid stenosis is thought to form as a result of intimal endothelial injury by mechanical hemodynamic shear stresses and metabolic and inflamma‐ tory processes. The plaque material often contains macrophages, inflammatory cells, calcium, lipid and cholesterol deposits, thought to be formed as part of the healing process after endothelial injury [1].

based on 2010 economic data and with the aging American population and higher incidence of obesity and diabetes in young adults, this cost to the American economy will increase [2]. An interesting analysis was published demonstrating that approximately 120 million neurons (equivalent to 714 kilometers or 444 miles of myelinated fibers) are lost each hour after a large arterial occlusion, thereby accelerating brain aging by 3.6 years per hour of ischemia time [3]. This neuronal loss often translates into permanent and devastating neurological sequelae.

It has been estimated that 20-30% of ischemic strokes result from extracranial carotid artery stenosis secondary to atherosclerotic disease [4,5]. Atherosclerosis is a chronic progressive process associated with modifiable risk factors that promote chronic inflammatory events within the arterial wall. Progression of atherosclerotic plaque formation causes ischemic stroke generally by one of two mechanisms: either a flow-limiting stenosis of the arterial lumen resulting in cerebral hypoperfusion typically in the watershed territories or more commonly, thromboembolic events from ruptured atherosclerotic plaque. Until one of these events causes

The prevalence of carotid stenosis can vary widely with geographic location due to cultural, genetic, and socioeconomic differences. The acquired nature of atherosclerotic disease implies that several of the risk factors that contribute to its development can be modified by individual

Important modifiable risk factors for developing carotid atherosclerotic disease include smoking, hypertension, dyslipidemia and poor glycemic control in diabetic patients. Smoking is strongly associated with development of carotid atherosclerotic disease whereby comparing age-matched non-smokers, former smokers and current smokers, the prevalence of clinically significant carotid stenosis (>50%) was seen in 4.4%, 7.3% and 9.5% (P<0.0001), respectively. Treatment of hypertension has been associated with reduced risk of developing carotid stenosis and stroke. For every 20mmHg increase in systolic blood pressure the odds ratio of developing moderate carotid stenosis is 2.11. Additionally, every 10mg/dL increase in serum cholesterol level was associated with an odds ratio of 1.10 for developing hemodynamically significant carotid stenosis. Strict control of postprandial glucose levels in diabetic patients has been associated with a reduction of carotid intimal media thickness and may also help to

It has been well established that carotid stenosis tends to occur at the bifurcation, which corresponds to vascular shear stresses as determined by *in vivo* measurements and *in vitro* flow models. The healthy artery is composed of three distinct layers, the tunica intima, tunica media and tunica adventitia, as seen from the lumen to the outer vessel wall. The tunica intima is

a stroke, carotid stenosis remains asymptomatic and often goes undetected.

changes in lifestyle, diet, and medical management.

206 Carotid Artery Disease - From Bench to Bedside and Beyond

reduce the incidence of stroke from carotid stenosis [6].

**4. Histopathology of atherosclerotic disease**

**3. Risk factors**

After disruption of the arterial endothelial lining, expression of inflammatory cell adhesion markers such as VCAM-1, ICAM and other receptors are upregulated [1,7]. Additionally, platelets adhere to the disrupted endothelium after balloon angioplasty and they degranu‐ late, thereby releasing various cytokines and growth factors including transforming growth factor beta (TGF-β), epidermal growth factor (EGF) and platelet derived growth factor (PDGF) [1,8].These resultinmigrationandproliferationofthevascular smoothmuscle cellsofthe tunica mediatoformaneointimallayerinanattempttohealthedisruptedendothelium.Thisneointima becomes more permeable to inflammatory cells as degranulated platelets adhere and remod‐ el the site of the injured intima [1,9,10]. T-cells, monocytes and lipid laden macrophages are seen in these plaques as they become more chronic, and calcium is often deposited during this process in an attempt to stabilize the plaque. Plaques with less calcification tend to be more vulnerable to rupture or thrombosis, indicating that the deposition of calcium appears to be protective and helps to stabilize the plaque by encasing the inflammatory materials,ratherthan leaving them exposed for further exacerbation of the inflammatory process [1,11].

The proliferation of smooth muscle cells is accompanied by an increase in matrix metallopro‐ teinases (MMPs) such as MMP-2 and MMP-9, which help to remodel the vessel by dilating the stenotic segment, thereby initially compensating for the loss of intimal diameter by the early plaque. However, with progression of the plaque thickness, the vessel eventually can no longer dilate further to compensate once the plaque occupies about 40-50% of the luminal diameter, and the lumen becomes progressively more narrowed [1].

Vascular stenosis alone does not appear to correlate well with predicting which asymptomatic plaques will result in cerebrovascular symptoms, and therefore additional information about the plaque characteristics are important to assess the vulnerability of the plaque to progress and become symptomatic. Factors which appear to be important in identifying vulnerable plaques include echolucency of the plaque on high resolution B-mode ultrasound, absence of calcification, presence of intraplaque hemorrhage, surface irregularity, fibrous cap thickness, plaque volume and presence and location of a necrotic core [12].
